Sie befinden Sich nicht im Netzwerk der Universität Paderborn. Der Zugriff auf elektronische Ressourcen ist gegebenenfalls nur via VPN oder Shibboleth (DFN-AAI) möglich. mehr Informationen...
Double Affinity Amplification of Galectin-Ligand Interactions through Arginine-Arene Interactions: Synthetic, Thermodynamic, and Computational Studies with Aromatic Diamido Thiodigalactosides
Ist Teil von
Chemistry : a European journal, 2008-01, Vol.14 (14), p.4233-4245
Ort / Verlag
Weinheim: WILEY-VCH Verlag
Erscheinungsjahr
2008
Link zum Volltext
Quelle
Wiley Online Library - AutoHoldings Journals
Beschreibungen/Notizen
A series of aromatic mono‐ or diamido‐thiodigalactoside derivatives were synthesized and studied as ligands for galectin‐1, ‐3, ‐7, ‐8N terminal domain, and ‐9N terminal domain. The affinity determination in vitro with competitive fluorescence‐polarization experiments and thermodynamic analysis by isothermal microcalorimetry provided a coherent picture of structural requirements for arginine–arene interactions in galectin–ligand binding. Computational studies were employed to explain binding preferences for the different galectins. Galectin‐3 formed two almost ideal arene–arginine stacking interactions according to computer modeling and also had the highest affinity for the diamido‐thiodigalactosides (Kd below 50 nM). Site‐directed mutagenesis of galectin‐3 arginines involved in binding corroborated the importance of their interaction with the aromatic diamido‐thiodigalactosides. Furthermore, the arginine mutants revealed distinct differences between free, flexible, and solvent‐exposed arginine side chains and tightly ion‐paired arginine side chains in interactions with aromatic systems.
Sticky situation: Arginine‐sticking aromatic structures (C2‐symmetrical and unsymmetrical thiodigalactoside derivatives with one or two aromatic amide substituents at the 3‐positions) display sensitivity to electronic and steric requirements and can provide selective nanomolar galectin‐3 inhibitors. This inhibition efficiency makes the inhibitors promising leads for the development of galectin‐targeting drugs.